The goal of this proposal is to implement and evaluate a full-featured solution for image-guided radiotherapy (IGRT) of small animals based on a microCT scanner. At present, the methods used to irradiate animal models of disease bear little resemblance to those routinely applied in the clinic. Through the development of radiotherapy techniques for small animals that approach the capabilities of clinical procedures, we will enable investigation of a variety of research questions relevant to clinical medicine as well as molecular biology. The feasibility of laboratory-based conformal radiotherapy has been demonstrated by preliminary investigations in my laboratory in which a variable aperture collimator has been added to a commercially available microCT system, generating a system capable of delivering radially convergent X-ray beams with circular profiles of arbitrary sizes to small animal subjects. In this project we will apply this novel technology towards the creation, evaluation, and preliminary application of a comprehensive method for imaging, treatment planning, and radiation delivery to small animals. Because this system will be developed as a hardware and software expansion for a commercial microCT scanner, it has the potential to be applied in biomedical research at a number of centers throughout the world at low cost. After generation of the system we will apply it in the study of radiotherapy in the treatment of orthotopic models of cancer, allowing evaluation of emerging therapeutic paradigms in a laboratory environment. These efforts will establish a new mechanism for exploring radiotherapy and radiobiology in the laboratory and will provide direct evidence of the merit of novel treatment regimens for use in designing clinical trials. In this research a system for treating small animals with clinically-similar image-guided conformal radiotherapy will be developed. The device, based on a commercially available microCT scanner, has the potential for widespread distribution and use within the scientific community, and will enable research of novel clinically- relevant radiation therapies and radiobiology in a laboratory. This research theme will be explored in this project by applying the system towards studying hypo- and hyper-fractionation schemes as well as hypoxia image-guided radiotherapy, providing data for subsequent clinical translation.